The mesocorticolimbic dopamine (DA) system has been implicated in mediating the rewarding effects of various drugs of abuse. An involvement of this system in the development of drug-induced tolerance, withdrawal and sensitization, phenomenon which are thought to play a role in drug-craving and relapse, has more recently been postulated. Evidence that opioidergic neurons can modulate the activity of this system has also been presented. Given the apparent involvement of both DAergic and opioidergic neurons in the addiction process, ongoing studies are seeking to determine: i) whether manipulations which alter their neuronal activity can modify the pharmacological and/or neurochemical effects of psychoactive drugs and ii) whether differences in the basal activity of DAergic and/or opioidergic systems or their responsivity to drugs of abuse underlie individual differences in compulsive drug-seeking behavior. Classical (place preference conditioning) and operant (drug discrimination, self-administration) conditioning techniques are being used to characterize the rewarding effects of opioids and psychostimulants and to identify pharmacological treatments which lead to or prevent the development of drug dependence and sensitization. In-vivo microdialysis combined with HPLC and electrochemical detection is being used to quantitate neurotransmitter release/metabolism within the mesocorticolimbic system in response to various psychoactive drugs. Identical studies using inbred rat strains as well as animals with a history of pre/post natal drug exposure are being conducted to identify those factors, both endogenous and exogenous which may underlie vulnerability to drug abuse.